Contribution of alterations in peritubular capillary density and microcirculation to the progression of tubular injury and kidney fibrosis.

Peritubular capillary (PTC) rarefaction is a common pathological feature of chronic kidney disease (CKD). The critical function of PTCs in maintaining blood supply for tubular epithelial cells renders PTCs a promising therapeutic target. However, the role of PTC rarefaction in the progression of kidney fibrosis remains elusive. In this study, we first characterized mice with altered PTC density. CD31 staining, together with microvascular network perfusion with FITC-labelled albumin and laser speckle contrast imaging, revealed a significant increase in PTC density in Flt1 heterozygous-deficient mice, whereas homozygous disruption of the plasminogen activator, urokinase receptor gene (Plaur/uPAR), led to a notable decrease in PTC density. Using these genetically distinct mice, we showed that preexisting higher PTC density protected against tubular injury and attenuated the progression of tubulointerstitial fibrosis in two distinct kidney injury models, namely, ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO). By contrast, Plaur-deficient mice with established lower PTC density displayed exacerbated tubular injury and renal fibrosis when subjected to IRI or UUO. The pathophysiological significance of PTC density was associated with protective effects on tubular cell apoptosis and concomitant regeneration. Finally, vasodilation of the renal capillary with minoxidil, a clinically available drug, effectively prevented UUO-induced tubular injury and renal fibrosis. Moreover, minoxidil treatment abolished the detrimental effect of Plaur deficiency on the UUO-treated kidney, thus suggesting a causative role of PTC density in the susceptibility of Plaur knockout mice to tubular injury following fibrosis. Our results provide an overview of the pathologic significance of PTC density alterations in the progression of CKD, and show that improving peritubular microcirculation is effective in preventing tubular injury and the subsequent renal fibrosis. © 2025 The Pathological Society of Great Britain and Ireland.